EP0161887A2 - Vernetzte Hyaluronsäure und ihre Verwendung - Google Patents

Vernetzte Hyaluronsäure und ihre Verwendung Download PDF

Info

Publication number
EP0161887A2
EP0161887A2 EP85303183A EP85303183A EP0161887A2 EP 0161887 A2 EP0161887 A2 EP 0161887A2 EP 85303183 A EP85303183 A EP 85303183A EP 85303183 A EP85303183 A EP 85303183A EP 0161887 A2 EP0161887 A2 EP 0161887A2
Authority
EP
European Patent Office
Prior art keywords
crosslinked
hyaluronic acid
salt
crosslinked hyaluronic
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP85303183A
Other languages
English (en)
French (fr)
Other versions
EP0161887A3 (en
EP0161887B1 (de
Inventor
Katukiyo C/O Tokyo Kenkyusho Sakurai
Yoshio C/O Tokyo Kenkyusho Ueno
Takashi C/O Tokyo Kenkyusho Okuyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Seikagaku Corp
Original Assignee
Seikagaku Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP59088440A external-priority patent/JP2501551B2/ja
Priority claimed from JP60004908A external-priority patent/JPS61164558A/ja
Priority claimed from JP60008512A external-priority patent/JPH0634814B2/ja
Priority claimed from JP60013595A external-priority patent/JPH0611694B2/ja
Priority claimed from JP5035785A external-priority patent/JPS61210034A/ja
Application filed by Seikagaku Corp filed Critical Seikagaku Corp
Publication of EP0161887A2 publication Critical patent/EP0161887A2/de
Publication of EP0161887A3 publication Critical patent/EP0161887A3/en
Application granted granted Critical
Publication of EP0161887B1 publication Critical patent/EP0161887B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/044—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair

Definitions

  • This invention relates to a crosslinked hyaluronic acid. More-particularly, it is concerned with a crosslinked hyaluronic acid or a salt thereof, which is prepared by crosslinking hyaluronic acid (hereinafter referred to as "HA") or a salt thereof with a polyfunctional epoxy compound.
  • HA crosslinking hyaluronic acid
  • HA is widely distributed in connective tissues such as skin, vitreous body or hyaloid, umbilical cord, synovial fluid, rooster comb and so on, like acidic mucopolysaccharides such as chondroitin sulfuric acid, heparan sulfuric acid, keratosulfuric acid.
  • connective tissues such as skin, vitreous body or hyaloid, umbilical cord, synovial fluid, rooster comb and so on, like acidic mucopolysaccharides such as chondroitin sulfuric acid, heparan sulfuric acid, keratosulfuric acid.
  • HA is present between cells as a complex with protein in tissue, forms a jelly matrix owing to high water retention and can play an important role in a living body such as in maintenance of cell morphology, or protection against attack by bacteria or external power, control of cellular metabolism, or lubricating action in joints (K. Meyer, Physiol. Rev., 27, 335, 1947
  • HA may exert a different action from mucopolysaccharides having a high charging property, which is believed to be derived from a different factor from a simple highly negative charging property, i.e., a high viscoelasticity of HA molecule.
  • HA as in a living body may form a complex with certain, special proteins, show a stable and strong stringiness and a high viscoelasticity and play a specific role, whereas the HA as isolated and purified hardly exhibits stringiness,and it was very difficult in the prior art-to extract and purify a highly viscous HA.
  • HA is known to undergo enzymatic decomposition or non-enzymatic oxidation-reduction decomposition after administration to a living body, especially diseased sites (W. Pigman, S. Pizvi and H. L. Holley, Arthritis Rheumatism, 4, 240, 1961) so that it would be difficult to maintain its original viscosity Therefore, satisfactory results have not yet been obtained.
  • crosslinked HA which shows resistance to enzymatic decomposition or non-enzymatic oxidation-reduction decomposition and, as a result, it has been found that the intended objects can be achieved by crosslinking HA,or a salt thereof,with a polyfunctional epoxy compound. Further, it has been found that the present crosslinked HA or salts thereof can also show resistance to hyaluronidase and keep various properties of HA itself and thus can have a ide variety of medical and cosmetic uses.
  • Another objectof this invention is to provide new uses of the present crosslinked HA as medicines, typically, an arthritis treating agent, a vitreous body treating agent or a medical molded product or as skin cosmetics.
  • the crosslinked HA,and salts thereof,according to this invention is a crosslinked HA which is prepared by crosslinking HA,or salts thereof,with a polyfunctional epoxy compound and, especially, characterized in that a crosslinking index or number is-5 or more per 1000 repeating disaccharides composed of glucuronic acid and N-acetylglucosamine of HA (hereinafter sometimes referred to as repeating disaccharides of HA).
  • the HA which may be employed in this invention may be any of those originating from various, non-limiting materials such as umbilical cord, rooster comb, vitreous body and so on may have usually a molecular weight of several thousands to several millions.
  • methods as disclosed in JP-A- 145594/1977, 145594/1977, 67100/1979 and 74796/1980.
  • alkali metal salt such as sodium or potassium salt
  • an alkaline earth metal salt such as calcium or magnesium salt.
  • polyfunctional epoxy compound is meant to indicate the compound which has at least one epoxy group and, further, one or more functional groups suitable for crosslinking hyaluronic acid including epoxy groups.
  • Such compounds may be exemplified by a halomethyloxirane compound, a bisepoxy compound and the like.
  • a halomethyloxirane compound there may be mentioned, for example, epichlorohydrin, epibromohydrin, ⁇ -methylepichlorohydrin, ⁇ -methylepibromohydrin and the like.
  • the bisepoxy compound there may be mentioned, for example, 1,2-bis(2,3-epoxypropoxy)ethane, 1,4- bis(2,3-epoxypropoxy)butane, 1,6-bis(2,3-epoxypropoxy)-hexane and a diglycidyl ether of bisphenol A or bisphenol F.
  • the crosslinked HA of this invention may be synthesized, for instance, according to the following procedures: usually, HA having a molecular weight of several thousands to several millions or a salt thereof is dissolved in an aqueous solution of an alkali to a concentration of not less than 0.5 %, preferably not less than 1.0 % and then a water-soluble organic solvent is added so as to amount to not less than 30 %, preferably not less than 50 %, of a whole liquid volume.
  • An aqueous alkali solution has preferably a pH of 8-14, more preferably a pH of 12-14.
  • the alkali there may be usually mentioned an alkali or alkaline earth metal hydroxide such as sodium hydroxide, potasisum hydroxide or caldium hydroxide; an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
  • the water-soluble organic solvent there may be mentioned, for example, methanol, ethanol, isopropanol, acetone or dioxane; it may be used alone or in combination therewith. Addition of such water-soluble organic solvent may achieve effective reaction proceeding and also prevent the HA from decomposition with an alkali or reduction of a molecular weight.
  • reaction period of time may vary depending upon the reaction temperature applied and 24 - 48 hours may be preferred at around 20 °C, while 2 - 3 hours may be suitable at around 40 °C.
  • a crosslinking index of the resulting crosslinked HA or salt thereof may be controlled by varying a molar ratio of the HA or salt thereof to the polyfunctional epoxy compound.
  • crosslinked HA wherein a crosslinking number is 5 or more per 1000 repeating disaccharides of HA, it is satisfactory to.employ one or more moles of the polyfunctional epoxy compound per mole of repeating disaceharide of HA.
  • HA having a molecular weight of approximately one million when 1 - 10 moles of the polyfunctional epoxy compound are employed to one more of repeating disaccharide of HA, there could be prepared a crosslinked HA having water solubility and stringiness (hereinafter frequently-referred to as ''s-crosslinked HA"; on the other hand, when not less than 10 moles of the epoxy compound are employed, there could be prepared a crosslinked HA having water insolubility and gel form (hereinafter frequently referred to as "is-crosslinked HA". Also, if one may use the HA having a molecular weight of approximately two millions, similar results could be obtained with 2 - 6 moles or not less than 6 moles of the epoxy compound, respectively.
  • the crosslinked HA which may be employed in this invention may also be prepared according to the following alternative procedures: To an alkali solution of the HA or salt thereof is added said water-soluble organic solvent and the resulting sticky precipitate is separated and then said polyfunctional epoxy compound is added. Then, reaction may be conducted at a temperature of 50 °c or lower to accomplish very efficient reaction.To obtain said sticky precipitate, one may apply decantation, for example, to remove supernatant. Reaction temperature is usually 10 - 50 °C, most preferably 20 - 40 °C. The higher the reaction temperature, the shorter reaction period should be. Generally, about 2 hours may be preferred at around 40 °C, while 24 - 48 hours may be suitable at around 20 ° C .
  • the s-crosslinked HA has a higher viscosity as compared with the starting HA and may usually have a viscosity of 650 - 60000 centipoises (cp) in a 1 % physiological saline solution (20 °C, slide speed, 1 sec -1 ) and a non-Newtonian index of 0.5 - 0.8 (See H. Kondo, "Kitasato Igaku", 10, 485, 1980).
  • cp centipoises
  • the crosslinked HA is usually dissolved in physiological saline to such a sufficient viscosity to pass through an-injection needle, namely not more than 50000 cp, preferably 5000 - 30000 cp (20 °C, shear rate 1 sec -1 ).
  • the present arthritis treating agent can show a high safety and a high resistance to tissue enzymes such as hyaluronidase etc. and may be useful for treatment..of various arthritides, e.g., arthritis deformans, chronic articular rheumatism and so on.
  • the crosslinked HA is dissolved in physiological saline so as to obtain a similar viscosity to that for arthritides.
  • Injection may be accomplished, for example, according to Scott method, injection under twin inverted image ophthalmologic scopic examination with silicon oil (J.D. Scott, Traus. Ophthalmol. Soc. U.K., 93, 417, 1973).
  • the present vitreous body agent may be applied to patients without taking the prone position.
  • the present agent may be useful for treatment of difficult retinal detachment to treat and restore, i.e., retinal ablation with proliferation retinopathy of vitreous body, retinal detachment with huge dehiscence, proliferation traction retinal detachment or dehiscence-originated retinal detachment with diabetic retinopathy.
  • the crosslinked HA may be preferably incorporated into cosmetics at 0.01 - 3 % upon a whole cosmetic composition.
  • the present cosmetics may be optionally blended with other cosmetic additives such as a water-soluble thickening agent, a surface active agent, an oil hymectant, an ultraviolet absorbing agent, an alcohol, a chelating agnet, a pH adjusting agent, an anseptic agent, a pigment and a perfume.
  • other cosmetic additives such as a water-soluble thickening agent, a surface active agent, an oil hymectant, an ultraviolet absorbing agent, an alcohol, a chelating agnet, a pH adjusting agent, an anseptic agent, a pigment and a perfume.
  • water-soluble thickening agnet may be _ mentioned, for example, a polyamino acid or a salf thereof; a polyacrylic acid or a salt thereof; pulurane; carboxymethylcellulose; xanthan gum and the like.
  • Such water-soluble thickening agent may be usually employed alone or in admixture with the two or more and may incorporated at 0.01 - 5 % into a cosmetic composition.
  • the present skin cosmetics may be blended with allantoin or its derivative which may be employed as a dermatological disease treating agent or a raw material for cosmetic industry. In this instance, it may be preferably incorporated at 0.01 - 5 %.
  • the present cosmetics can show an excellent water retention and an excellent resistance to enzymes.
  • the present cosmetics may be applied, for example, after shaving, to chaps cracks, chapped skin and so on in the form of cosmetics such as creams, e.g. a nutrient cream, a hand cream, a body cream, a massage cream; nutrient milky lotions; face packs; face lotions, as well as hair cosmatics.
  • creams e.g. a nutrient cream, a hand cream, a body cream, a massage cream
  • nutrient milky lotions e.g. a nutrient milk, a hand cream, a body cream, a massage cream
  • nutrient milky lotions e.g. a nutrient milky lotions
  • face packs e.g. a hair cosmatics.
  • the present molding material In molding a medical molded product with the present molding material, the present molding material is placed into a desired die, dehydrated and then dried.
  • a molded product may be of any shape, preferably in the shape of a film. There is; no limitation to molding procedures and casting is preferable.
  • An aqueous solution or suspension of the present molding material may be coated over a polymer, i.g., polyethylene sheet or film or a support, e.g., glass or metal plate to a desired thickness by means of an applicator, dehydrated and dried and then peeled off from said sheet, film or support to produce a film molded product.
  • a polymer i.g., polyethylene sheet or film or a support, e.g., glass or metal plate
  • a medical molded product obtained from the present molding material when dipped in water or physiological saline may gradually absorb water and may be dissolved.
  • the dissolved product may be decomposed with enzymes and the like and, therefore, if a crosslinking index may be controlled, it could be present within a living body or skin only over a necessary period and dissolved away from tissues as lacked tissues will be healed.
  • the present crosslinked HA when given or applied to a living body, does not show any foreign body reaction and, when applied as a medical molded product, can show a very high safety.
  • Fig. 2 the hollow circle ( ⁇ ), full circle (•), hollow square (a) and full square ( ⁇ ) show viscosities, respectively, 1 % physiological saline solutions of the s-crosslinked HA and the HA as well as synovia of normal human and that of patient with light arthritis deformans at various shear rates.
  • the s-crosslinked HA as synthesized in the above (1) was tested for its analgesic effect as stated below.
  • Beagle dogs irrespective of male and female, were given at the knee joint of either hind leg with 20 ⁇ g or 2 mg of bradykinin or acetylcholine as a pain substance together with a physiological saline solution containing the s-crosslinked HA at 2.5 mg/0.5 ml and then changes in medicated hind leg loading were measured with lapse of time. Also, a physiological saline solution containing the HA sodium salt at 5 mg/0.5 ml as used as a starting material in the above (1) was used as a control instead of the s-crosslinked HA solution. Analgesic effect was compared with 50 % load recovery time at a normal time. The results are shown in Table 1.
  • Example 1 (1) Following the same procedures as in Example 1 (1) except that there was employed as a starting material HA sodium salt with a molecular weight of 7.3 x 10 5 , there were synthesized 3 sorts of the following s-crosslinked HA:
  • Viscosity of a 1 % O.lM acetic acid (pH 5.0) solution of said s-crosslinked HA or HA sodium salt used for synthesis was measured (20 ° C , slide speed 1.0 sec- 1 ) to give the following results;
  • Fig. 4 hollow square ( ⁇ ), hollow triangle ( ⁇ ), hollow circle ( ⁇ ) and full circle (•) represents ratios to viscosity before reaction at various reaction times in acetic acid solutions of s-crosslinked HA (A), (B) and (C) and HA sodium salt.
  • the is-crosslinked HA as synthesized in the above (1) was weighed at 10.00, 5.56, 2.94, 2.00, 1.67 and 1.25 mg and suspended in 15 ml of 0.00167M acetic acid.
  • To the suspensions was added and throughly admixed each 1.0 ml of a 0.00167 acetic acid solution of 0.5 % collagen (obtained and purified by dissolving bovine derma collagen with pepsin). The resulting mixture was stirred well for 10 minutes and then centrifuged at 3000 rpm. The precipitate was washed well with 0.00167M acetic acid, collagen was dissolved out with 2M-guanidine-hydrochloric acid (pH 7.0) and quantitatively determined according to Procop method.
  • HA red sodium borohydride
  • each stirring for 30 minutes and centrifugation at 3000 rpm was effected in turn with each 200 ml of a 0.5M aqueous solution of sodium chloride, 1.0M-guanidine ⁇ hydrochloric acid (pH 7.0), 2.0M-guanidine-hydrochloric acid (pH 7.0) and 5.0M-guanidine ⁇ hydrochloric acid.
  • Each supernatant was quantitatively determined for uronic acid according to carbazole-sulfuric acid method to measure a proteoglycan amount. The results are shown in Table 2.
  • mice of 4 weeks of age were preliminarily fed over 1 week. At the begining of test, a body weight of mice was 21 - 27 g.
  • mice were divided into groups, each group consisting of 15 animals.
  • To each group was intraperitoneally administered the s-crosslinked HA of Example 1 in the form of a 0.5 % physiological saline solution thereof at 1 ml/10 g of body weight (500 mg/kg), a 1 % physiological saline solution thereof at 1 ml/10 g of body weight (1000 mg/kg) or a physiological saline solution at 1 ml/10 g of body weight.
  • Each 1.5 % aqueous solution of above HA was coated over a polyvinyl chloride plate to a certain thickness by means of an applicator and dehydrated by heating with a hot air at 40 °C for 20 hours. Each coated film was peeled off to form a film with a thickness of 0.003 cm. Also, a 1.5 % aqueous solution of HA (molecular weight, 800000) was treated in the same manner as above to form a HA film with a thickness of 0.003 cm as control.
  • Tensile resistance of the film was measured by means of Tensitron all-purpose tester RTM-50 (available from Toyo-Baldwin K.K.). ' The results are shown in Table 6.
  • test tube 10 ml of physiological saline and the resulting mixture was allowed to stand for 30 minutes. Test tube was vigorously shaken up and down 20 times and then allowed to stand for one day. Again, test tube was vigorously shaken up and down 20 times and then centrifuged at 3000 rpm for 30 minutes. 0.1 ml of supernatant was recovered and determined for uronic acid according to carbazole-sulfuric acid method to determine elution rate.
  • test tube was vigorously shaken up and down 20 times and then allowed to stand for one day. Thereafter, elution rate was determined in the smae manner as above. The aforesaid procedures were repeated for 18 days. The results are shown in Fig. 6.
  • full circle (•), hollow circle ( 0 ), X mark and dotted circle ( ) represent, respectively, elution rates after 1, 2, 3 and 18 days.
  • the HA film was completely dissolved when allowed to stand at the first 30 minutes period.
  • Each 7.6 mg of the crosslinked HA-1 film and HA film as in the above (1) was embedded into 10 male Hartley strain guinea pigs with 4 weeks of age (an average body weight of 250 g) under the skin of back, incision part was sutured with nylon threads of 5 - 6 needles and then disinfected. After the 2nd, 5th, 10th and 20th days from transplantation, guinea pigs were killed with ether and then tissue with 3 x 4 cm was taken out from the under part of the subcutaneous layer of transplanted sites. The tissue thus taken was dipped and extracted into 40 ml of a 4M aqueous solution of guanidine at room temperature for 24 hours under stirring. As control, the tissue of the same part in non-treated guinea pigs was similarly treated.
  • a storage period of crosslinked HA in living body may be optionally controlled by controlling crosslinking index in crosslinked HA.
  • the experimental apparatus provided with a pendulum as shown in Fig. 8 is to record electrical signals corresponding to inclinational angles of an artificial hip joint, which angles are measured by an inclinometer which is set right above the artificial hip joint supported on the central upper portion of the pendulum.
  • the inclinational angle is converted into the corresponding electrical signal.
  • the artificial hip joint is composed of ceramic sphere or ceramic porous ball.
  • the fluid lubrication time was measured with respect to HA having no stringiness, and normal human joint fluid and crosslinked HA-1 both having stringiness.
  • HA a sample having a molecular weight of 85 x 10 4 was used in physiological saline solutions having concentrations of 0.25, 0.5, 0.75, 1.5 and 2.0 .%, respectively.
  • Crosslinked HA-1 was used as a 0.5 % solution in a physiological saline.
  • a sample having an HA concentration of 3.4 mg/ml was used.
  • a porous sphere was filled with a test liquid as the lubricating fluid, and the fluid lubrication time was measured by starting the free swinging with an intial amplitude of 5 rad immediately after loading with 2 kg and then recording the angle variation with the lapse of time as a swinging wave pattern.
  • FIG. 9 An example of the thus obtained wave pattern is shown in Fig. 9, in which the rigion A corresponds to fluid lubrication and the region B corresponds to boader line lubrication.
  • a crosslinked HA-1 having stringiness acts advantageously as a fluid lubricant which contributes to the lubrication mechanism of a joint.
  • NF ⁇ SF normal human joint fluid
  • OA-SF osteoarthritis joint fluid
  • the stringinesses of NF ⁇ SF and OA ⁇ SF were measured by adding HA (having a molecular weight of 7.3 x 10 5 ) and crosslinked HA-1 to NH ⁇ SF and OA ⁇ SF, respectively, so that the concentrations thereof might be 0.35 %.
  • NH ⁇ SF was treated by a hyarulonidase immobilized on a formylcellulofine (manufactured by Chissokogyo K.K., Japan), and to the thus obtained treated solution(hereinafter referred to as NF ⁇ SF deg HA) was added HA or crosslinked HA so that the conceantration thereof might be 0.35 % to measure the strin g iness thereof.
  • the stringiness was measured by using a Watanabe type apparatus for measuring stringiness (see Ideuchi, Nippon Seikeigeka Zasshi 34, 175 (1962).
  • the draw-up-speed was set to be 7 cm/sec.
  • OA ⁇ SF shows small stringiness due to the HA having its molecular weight reduced, or being defficient, or to the defficiency of a protein or proteins to be bonded with HA. Therefore, it can be understood that it is very effective to introduce a crosslinked HA having stringiness to a diseased joint.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP85303183A 1984-05-04 1985-05-03 Vernetzte Hyaluronsäure und ihre Verwendung Expired - Lifetime EP0161887B1 (de)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
JP88440/84 1984-05-04
JP59088440A JP2501551B2 (ja) 1984-05-04 1984-05-04 架橋ヒアルロン酸
JP60004908A JPS61164558A (ja) 1985-01-17 1985-01-17 医療用成形物の成形材料
JP4908/84 1985-01-17
JP60008512A JPH0634814B2 (ja) 1985-01-22 1985-01-22 硝子体適用剤
JP8512/84 1985-01-22
JP13595/84 1985-01-29
JP60013595A JPH0611694B2 (ja) 1985-01-29 1985-01-29 皮膚化粧料
JP5035785A JPS61210034A (ja) 1985-03-15 1985-03-15 関節症治療剤
JP50357/85 1985-03-15

Publications (3)

Publication Number Publication Date
EP0161887A2 true EP0161887A2 (de) 1985-11-21
EP0161887A3 EP0161887A3 (en) 1986-10-08
EP0161887B1 EP0161887B1 (de) 1991-09-04

Family

ID=27518544

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85303183A Expired - Lifetime EP0161887B1 (de) 1984-05-04 1985-05-03 Vernetzte Hyaluronsäure und ihre Verwendung

Country Status (3)

Country Link
US (1) US4716224A (de)
EP (1) EP0161887B1 (de)
DE (1) DE3583963D1 (de)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0224987A2 (de) * 1985-11-29 1987-06-10 Biomatrix, Inc. Arzneistoffabgabesysteme auf Basis von Hyaluronan, dessen Derivaten und Salzen sowie Verfahren zu deren Herstellung
WO1987007898A1 (en) * 1986-06-18 1987-12-30 Pharmacia Ab Material of polysaccharides containing carboxyl groups, and a process for producing such polysaccharides
GB2207142A (en) * 1987-06-11 1989-01-25 Skandigen Ab Hyaluronic acid derivatives and their production
WO1989001777A1 (en) * 1987-08-25 1989-03-09 Macnaught Pty. Limited Lubricant composition for rheumatism
AU596838B2 (en) * 1986-04-28 1990-05-17 Mobay Corporation Remote administration of hyaluronic acid to mammals
US4957744A (en) * 1986-10-13 1990-09-18 Fidia, S.P.A. Cross-linked esters of hyaluronic acid
US5633001A (en) * 1993-03-19 1997-05-27 Medinvent Composition and a method for tissue augmentation
US5827937A (en) * 1995-07-17 1998-10-27 Q Med Ab Polysaccharide gel composition
WO1999056799A1 (en) * 1998-05-04 1999-11-11 Hibiscus S.R.L. Stabilised compositions containing hyaluronic acid, their preparation and use
WO2000046252A1 (en) * 1999-02-05 2000-08-10 Vitrolife Uk Limited Process for cross-linking hyaluronic acid to polymers
WO2000046253A1 (en) * 1999-02-03 2000-08-10 Vitrolife Uk Limited Process for the production of multiple cross-linked hyaluronic acid derivatives
WO2002006350A1 (fr) * 2000-07-19 2002-01-24 Laboratoires D'esthetique Appliquee Reticulation de polysaccharide(s), preparation d'hydrogel(s), polysaccharide(s) et hydrogel(s) obtenu(s), leurs utilisations.
FR2865737A1 (fr) * 2004-02-03 2005-08-05 Anteis Sa Gel reticule biocompatible
US7651702B2 (en) 2004-05-20 2010-01-26 Mentor Corporation Crosslinking hyaluronan and chitosanic polymers
DE102008053892A1 (de) 2008-10-30 2010-05-06 Fachhochschule Gelsenkirchen Medizinisches Implantat mit biofunktionalisierter Oberfläche
WO2012089179A1 (en) 2010-12-31 2012-07-05 Contipro Biotech S.R.O. Hyaluronan fibres, method of preparation thereof and use thereof
WO2013021249A1 (en) 2011-08-10 2013-02-14 Glycores 2000 S.R.L. Degradation-resistant cross-linked, low-molecular-weight hyaluronate
US8481080B2 (en) 2004-11-24 2013-07-09 Novozymes Biopolymer A/S Method of cross-linking hyaluronic acid with divinulsulfone
EP2644623A1 (de) * 2012-03-26 2013-10-02 Genewel Co., Ltd Implantationsmaterial mit biokompatiblem Polymer
WO2014056841A1 (en) 2012-10-09 2014-04-17 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Modified hyaluronic acid derivatives and use thereof
US9403918B2 (en) 2009-12-11 2016-08-02 Contipro Pharma A.S. Oxidized derivative of hyaluronic acid, a method of preparation thereof and a method of modification thereof
US9434791B2 (en) 2009-12-11 2016-09-06 Contipro Pharma A.S. Method of preparation of an oxidized derivative of hyaluronic acid and a method of modification thereof
US9492586B2 (en) 2012-02-28 2016-11-15 Contipro Biotech S.R.O. Derivatives of hyaluronic acid capable of forming hydrogels
US9522966B2 (en) 2012-08-08 2016-12-20 Contipro Biotech S.R.O. Hyaluronic acid derivative, method of preparation thereof, method of modification thereof and use thereof
US9597277B2 (en) 2006-12-22 2017-03-21 Croma-Pharma Gesellschaft M.B.H. Use of polymers
US9999678B2 (en) 2012-11-27 2018-06-19 Contipro A.S. C6-C18-acylated derivative of hyaluronic acid and method of preparation thereof
US10023658B2 (en) 2014-03-11 2018-07-17 Contipro A.S. Conjugates of oligomer of hyaluronic acid or of a salt thereof, method of preparation thereof and use thereof
US10414832B2 (en) 2015-06-26 2019-09-17 Contipro A.S Derivatives of sulfated polysaccharides, method of preparation, modification and use thereof
WO2020039008A1 (fr) * 2018-08-22 2020-02-27 Natvi Procédé de lubrification
US10618984B2 (en) 2016-06-27 2020-04-14 Contipro A.S. Unsaturated derivatives of polysaccharides, method of preparation thereof and use thereof
US10617711B2 (en) 2014-06-30 2020-04-14 Contipro A.S. Antitumor composition based on hyaluronic acid and inorganic nanoparticles, method of preparation thereof and use thereof
US10689464B2 (en) 2015-03-09 2020-06-23 Contipro A.S. Self-supporting, biodegradable film based on hydrophobized hyaluronic acid, method of preparation and use thereof
US10759878B2 (en) 2015-06-15 2020-09-01 Contipro A.S. Method of crosslinking of polysaccharides using photoremovable protecting groups

Families Citing this family (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4851521A (en) * 1985-07-08 1989-07-25 Fidia, S.P.A. Esters of hyaluronic acid
US5202431A (en) * 1985-07-08 1993-04-13 Fidia, S.P.A. Partial esters of hyaluronic acid
US4879114A (en) * 1985-12-20 1989-11-07 Angio-Medical Corporation Lipids from omentum and methods for cosmetic use
ATE66133T1 (de) * 1987-05-20 1991-08-15 Ueno Seiyaku Oyo Kenkyujo Kk Kondom.
US5783691A (en) * 1989-02-08 1998-07-21 Biomatrix, Inc. Crosslinked hyaluronate gels, their use and method for producing them
CA1340994C (en) * 1989-09-21 2000-05-16 Rudolf Edgar Dr. Falk Treatment of conditions and disease
US5627162A (en) * 1990-01-11 1997-05-06 Gwon; Arlene E. Methods and means for control of proliferation of remnant cells following surgery
US5990096A (en) * 1990-09-18 1999-11-23 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
US5910489A (en) * 1990-09-18 1999-06-08 Hyal Pharmaceutical Corporation Topical composition containing hyaluronic acid and NSAIDS
US5824658A (en) * 1990-09-18 1998-10-20 Hyal Pharmaceutical Corporation Topical composition containing hyaluronic acid and NSAIDS
US5639738A (en) * 1992-02-20 1997-06-17 Hyal Pharmaceutical Corporation Treatment of basal cell carcinoma and actinic keratosis employing hyaluronic acid and NSAIDs
CA2061703C (en) * 1992-02-20 2002-07-02 Rudolf E. Falk Formulations containing hyaluronic acid
US5705178A (en) * 1991-05-31 1998-01-06 Gliatech, Inc. Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers
US5605938A (en) * 1991-05-31 1997-02-25 Gliatech, Inc. Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate
US5234914A (en) * 1991-06-11 1993-08-10 Patent Biopharmaceutics, Inc. Methods of treating hemorrhoids and anorecial disease
US5792753A (en) * 1991-07-03 1998-08-11 Hyal Pharmaceutical Corporation Compositions comprising hyaluronic acid and prostaglandin-synthesis-inhibiting drugs
US5817644A (en) * 1991-07-03 1998-10-06 Hyal Pharmaceutical Corporation Targeting of dosages of medicine and therapeutic agents
US6022866A (en) * 1991-07-03 2000-02-08 Hyal Pharmaceutical Corporation Use of hyaluronic acid and forms to prevent arterial restenosis
WO1994007505A1 (en) * 1991-07-03 1994-04-14 Norpharmco Inc. Use of hyaluronic acid and forms to prevent arterial restenosis
US5977088A (en) * 1991-07-03 1999-11-02 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
US5990095A (en) * 1991-07-03 1999-11-23 Hyal Pharmaceutical Corporation Use of hyaluronic acid and forms to prevent arterial restenosis
US6103704A (en) * 1991-07-03 2000-08-15 Hyal Pharmaceutical Corporation Therapeutic methods using hyaluronic acid
JP2855307B2 (ja) * 1992-02-05 1999-02-10 生化学工業株式会社 光反応性グリコサミノグリカン、架橋グリコサミノグリカン及びそれらの製造方法
US6218373B1 (en) 1992-02-20 2001-04-17 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
US6136793A (en) * 1992-02-20 2000-10-24 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
US5767106A (en) * 1992-02-21 1998-06-16 Hyal Pharmaceutical Corporation Treatment of disease and conditions associated with macrophage infiltration
US5681825A (en) * 1993-03-15 1997-10-28 Lindqvist; Bengt Surgical method
US5531716A (en) * 1993-09-29 1996-07-02 Hercules Incorporated Medical devices subject to triggered disintegration
US5690961A (en) * 1994-12-22 1997-11-25 Hercules Incorporated Acidic polysaccharides crosslinked with polycarboxylic acids and their uses
US5612321A (en) * 1995-06-22 1997-03-18 Hercules Incorporated Antioxidant grafted polysaccharides
US6060534A (en) 1996-07-11 2000-05-09 Scimed Life Systems, Inc. Medical devices comprising ionically and non-ionically crosslinked polymer hydrogels having improved mechanical properties
US6368356B1 (en) 1996-07-11 2002-04-09 Scimed Life Systems, Inc. Medical devices comprising hydrogel polymers having improved mechanical properties
EP2002846B1 (de) 1996-12-06 2017-01-25 Amgen Inc. Kombinationstherapie mit einem IL-1-Inhibitor zur Behandlung von IL-1-vermittelten Krankheiten
US5804594A (en) * 1997-01-22 1998-09-08 Murad; Howard Pharmaceutical compositions and methods for improving wrinkles and other skin conditions
US6294170B1 (en) 1997-08-08 2001-09-25 Amgen Inc. Composition and method for treating inflammatory diseases
IT1303738B1 (it) * 1998-11-11 2001-02-23 Aquisitio S P A Processo di reticolazione di polisaccaridi carbossilati.
ES2223583T3 (es) 1999-07-28 2005-03-01 United States Surgical Corporation Barrera antiadherente de acido hialuronico.
WO2001013865A1 (en) 1999-08-20 2001-03-01 Howard Murad Pharmaceutical compositions and methods for reducing the appearance of cellulite
US20030224071A1 (en) * 1999-08-20 2003-12-04 Howard Murad Pharmaceutical compositions and methods for managing connective tissue ailments
EP1292314A2 (de) * 2000-05-23 2003-03-19 The Trustees of Columbia University in the City of New York Methode zur behandlung von krankheiten der atemwege durch einsatz von glycosaminoglycane
US6610810B2 (en) 2001-03-13 2003-08-26 Glyn Owen Phillips Biopolymers obtained by solid state irradiation in an unsaturated gaseous atmosphere
US6913765B2 (en) * 2001-03-21 2005-07-05 Scimed Life Systems, Inc. Controlling resorption of bioresorbable medical implant material
US6812211B2 (en) * 2002-03-19 2004-11-02 Michael Andrew Slivka Method for nonsurgical treatment of the intervertebral disc and kit therefor
US20050209699A1 (en) * 2002-03-19 2005-09-22 Slivka Michael A Method for nonsurgical treatment of the nucleus pulposus of the intervertebral disc using genipin or proanthrocyanidin, and kit therefor
TWI251596B (en) * 2002-12-31 2006-03-21 Ind Tech Res Inst Method for producing a double-crosslinked hyaluronate material
US20040180025A1 (en) * 2003-03-12 2004-09-16 New Life Resources, Llc Therapeutic, nutraceutical and cosmetic applications for eggshell membrane and processed eggshell membrane preparations
US20080063677A1 (en) * 2004-03-10 2008-03-13 New Life Resources, Llc Therapeutic, nutraceutical and cosmetic applications for eggshell membrane and processed eggshell membrane preparations
US6946551B2 (en) * 2003-03-12 2005-09-20 New Life Resources, Llc Preparation of hyaluronic acid from eggshell membrane
DE102004002001A1 (de) * 2004-01-14 2005-08-11 Reinmüller, Johannes, Dr.med. Mittel zur Behandlung von entzündlichen Erkrankungen
US8580315B2 (en) * 2004-03-10 2013-11-12 Esm Technologies, Llc Anti-inflammatory activity of eggshell membrane and processed eggshell membrane preparations
CZ297658B6 (cs) * 2004-05-06 2007-02-28 Cpn Spol. S R. O. Zpusob prípravy derivátu hyaluronanu vázaných karbamátovou vazbou
CZ297711B6 (cs) * 2004-05-06 2007-03-07 Cpn Spol. S R. O. Zpusob prípravy derivátu hyaluronanu vázaných éterovou nebo aminovou vazbou
ITMI20041373A1 (it) 2004-07-09 2004-10-09 Lima Lto S P A N-metil-ammidi di carbossimetilcellulosa acido alginico o carbossimetalamido
HUE025255T2 (en) * 2004-12-30 2016-03-29 Genzyme Corp Intraarticular viscosity implementation schemes
GB2423252B (en) * 2005-02-18 2007-10-17 Engelhard Lyon Cross-linked polymer of carbohydrate, notably based on polysaccharides, and/or on oligosaccharides and/or on polyols
US7674781B2 (en) * 2006-04-28 2010-03-09 Heather Sheardown Hyaluronic acid-retaining polymers
CN101522164B (zh) * 2006-09-13 2014-03-26 提升肤质产品公司 用于治疗皮肤的化妆品组合物及其方法
CN101153061A (zh) * 2006-09-29 2008-04-02 北京普麦迪克生物技术研究所 一种透明质酸及其二次交联形成凝胶的方法
ES2381417T3 (es) * 2007-09-28 2012-05-28 Shiseido Company, Ltd. Polvo de ácido hialurónico reticulado hinchable y procedimiento para fabricarlo
WO2009043111A1 (en) * 2007-10-04 2009-04-09 Ultraceuticals R & D Pty Ltd Composition and method for dermal regeneration
EP2222715B1 (de) 2007-12-19 2019-07-24 Evonik Degussa GmbH Vernetzte hyaluronsäure in einer emulsion
DE102007062113B4 (de) 2007-12-21 2011-05-12 Bettina Lingenfelder Dermatologische Zubereitung
PL2236523T3 (pl) 2009-03-30 2018-07-31 Scivision Biotech Inc. Sposób wytwarzania usieciowanego kwasu hialuronowego
US9371402B2 (en) 2009-04-09 2016-06-21 Scivision Biotech Inc. Method for producing cross-linked hyaluronic acid
FR2968306B1 (fr) * 2010-12-06 2014-02-28 Teoxane Procede de preparation d'un gel reticule
US20160310522A1 (en) * 2011-04-26 2016-10-27 AiMeike Technology Deveolpment., LTD Method for producing composite gel by cross-linking hyaluronic acid and hydroxylpropyl methylcellulose
WO2012146031A1 (zh) * 2011-04-26 2012-11-01 北京爱美客生物科技有限公司 透明质酸与羟丙基甲基纤维素复合凝胶及制备方法
FR2983483B1 (fr) 2011-12-02 2014-11-14 Vivacy Lab Procede de substitution et reticulation simultanees d'un polysaccharide via ses fonctions hydroxyles
TWI424007B (zh) * 2011-12-22 2014-01-21 Ind Tech Res Inst 使膠體交聯的方法與藉由此方法形成之經交聯的膠體
US9623157B2 (en) * 2013-03-15 2017-04-18 Lake Region Manufacturing, Inc. Modified hyaluronate hydrophilic compositions, coatings and methods
US9205105B2 (en) * 2013-05-22 2015-12-08 John Ascencion Campa, Iii Indication and technique for the use of cross-linked hyaluronic acid in the management of pain
US10077320B2 (en) * 2013-06-28 2018-09-18 Galderma S.A. Process for preparing a cross-linked hyaluronic acid product
WO2016129967A1 (ko) * 2015-02-13 2016-08-18 주식회사 엔도더마 가교된 히알루론산 하이드로젤을 이용한 마이크로구조체 및 이의 제조방법
EP3165233B1 (de) 2015-08-28 2021-08-18 Latvijas Universitate Biomaterial zur behandlung von akuten und chronischen hautwunden
KR20170090965A (ko) * 2016-01-29 2017-08-08 한미약품 주식회사 복합 히알루론산 가교물 및 그 제조방법
ITUA20161822A1 (it) * 2016-03-18 2017-09-18 Indena Spa Composizioni utili nella prevenzione e/o nel trattamento di patologie del cavo orale, delle prime vie aeree e dell’esofago
AU2018240375C1 (en) 2017-03-22 2024-02-01 Ascendis Pharma A/S Hydrogel cross-linked hyaluronic acid prodrug compositions and methods
WO2021020950A1 (ko) 2019-08-01 2021-02-04 하유진 히알루론산과 플루로닉을 포함하는 관절 및 연골 손상 예방 또는 치료용 조성물
WO2023030435A1 (en) 2021-09-01 2023-03-09 Shanghai Qisheng Biological Preparation Co., Ltd. Cartilage regeneration using injectable, in situ polymerizable collagen compositions containing chondrocytes or stem cells
CZ2021563A3 (cs) * 2021-12-14 2023-03-22 Contipro A.S. Derivát kyseliny hyaluronové se sníženou polaritou, způsob jeho přípravy, kompozice a použití

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1924900A1 (de) * 1969-05-16 1970-11-19 Frederick Kunz And Company Ltd Verfahren zur Querverknuepfung von Hemizellulosen aus Nahrungsmitteln
US4013629A (en) * 1975-02-21 1977-03-22 Krause Milling Company Art of catalyzing the reaction between a polyol and a polyaldehyde
US4470975A (en) * 1977-10-21 1984-09-11 The Johns Hopkins University Method and composition for the elimination of water from an animal body
JPS57185208A (en) * 1981-05-07 1982-11-15 Shiseido Co Ltd Skin cosmetic
JPS6084225A (ja) * 1983-10-17 1985-05-13 Hiroko Shimizu 点眼剤
US4532267A (en) * 1984-02-15 1985-07-30 Board Of Regents, University Of Washington Vision correction lens made from an aminopolysaccharide compound or an ether or ester thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ACTA CHEMICA SCANDINAVICA, vol. 18, part I, 1964, pages 274-275, published by Chemical Societies in Denmark, Finland, Norway and Sweden, editor K. Mybr{ck et al.; T.C. LAURENT et al.: "Cross-linked gels of hyaluronic acid" *

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0224987A2 (de) * 1985-11-29 1987-06-10 Biomatrix, Inc. Arzneistoffabgabesysteme auf Basis von Hyaluronan, dessen Derivaten und Salzen sowie Verfahren zu deren Herstellung
EP0224987A3 (en) * 1985-11-29 1987-11-19 Biomatrix, Inc. Drug delivery systems based on hyaluronan, derivatives thereof and their salts and method of producing same
AU596838B2 (en) * 1986-04-28 1990-05-17 Mobay Corporation Remote administration of hyaluronic acid to mammals
WO1987007898A1 (en) * 1986-06-18 1987-12-30 Pharmacia Ab Material of polysaccharides containing carboxyl groups, and a process for producing such polysaccharides
US4963666A (en) * 1986-06-18 1990-10-16 Pharmacia Ab Material of polysaccharides containing carboxyl groups, and a process for producing such polysaccharides
US4957744A (en) * 1986-10-13 1990-09-18 Fidia, S.P.A. Cross-linked esters of hyaluronic acid
GB2207142A (en) * 1987-06-11 1989-01-25 Skandigen Ab Hyaluronic acid derivatives and their production
GB2207142B (en) * 1987-06-11 1990-10-31 Skandigen Ab Hyaluronic acid derivatives and their production
WO1989001777A1 (en) * 1987-08-25 1989-03-09 Macnaught Pty. Limited Lubricant composition for rheumatism
US5633001A (en) * 1993-03-19 1997-05-27 Medinvent Composition and a method for tissue augmentation
US5827937A (en) * 1995-07-17 1998-10-27 Q Med Ab Polysaccharide gel composition
WO1999056799A1 (en) * 1998-05-04 1999-11-11 Hibiscus S.R.L. Stabilised compositions containing hyaluronic acid, their preparation and use
WO2000046253A1 (en) * 1999-02-03 2000-08-10 Vitrolife Uk Limited Process for the production of multiple cross-linked hyaluronic acid derivatives
EP1149116B2 (de) † 1999-02-03 2016-03-30 Mentor Biopolymers Limited Verfahren zur herstellung von mehrfach vernetzten hyaluronsäurederivaten
US8080641B2 (en) 1999-02-03 2011-12-20 Mentor Worldwide Llc Process for the production of multiple cross-linked hyaluronic acid derivatives
US7385052B2 (en) 1999-02-03 2008-06-10 Mentor Biopolymers Ltd. Process for the production of multiple cross-linked hyaluronic acid derivatives
US7514541B2 (en) 1999-02-03 2009-04-07 Mentor Corporation Process for the production of multiple cross-linked hyaluronic acid derivatives
WO2000046252A1 (en) * 1999-02-05 2000-08-10 Vitrolife Uk Limited Process for cross-linking hyaluronic acid to polymers
US6703444B2 (en) 1999-02-05 2004-03-09 A-Life Limited Process for cross-linking hyaluronic acid to polymers
US7226972B2 (en) 1999-02-05 2007-06-05 Mentor Biopolymers Limited Process for cross-linking hyaluronic acid to polymers
WO2002006350A1 (fr) * 2000-07-19 2002-01-24 Laboratoires D'esthetique Appliquee Reticulation de polysaccharide(s), preparation d'hydrogel(s), polysaccharide(s) et hydrogel(s) obtenu(s), leurs utilisations.
FR2811996A1 (fr) * 2000-07-19 2002-01-25 Corneal Ind Reticulation de polysaccharide(s), preparation d'hydrogel(s) ; polysaccharide(s) et hydrogel(s) obtenus,leurs utilisations
US8052990B2 (en) 2004-02-03 2011-11-08 Anteis S.A. Biocompatible crosslinked gel
WO2005085329A1 (fr) * 2004-02-03 2005-09-15 Anteis S.A. Gel reticule biocompatible
FR2865737A1 (fr) * 2004-02-03 2005-08-05 Anteis Sa Gel reticule biocompatible
US7651702B2 (en) 2004-05-20 2010-01-26 Mentor Corporation Crosslinking hyaluronan and chitosanic polymers
US8481080B2 (en) 2004-11-24 2013-07-09 Novozymes Biopolymer A/S Method of cross-linking hyaluronic acid with divinulsulfone
US9597277B2 (en) 2006-12-22 2017-03-21 Croma-Pharma Gesellschaft M.B.H. Use of polymers
DE102008053892A1 (de) 2008-10-30 2010-05-06 Fachhochschule Gelsenkirchen Medizinisches Implantat mit biofunktionalisierter Oberfläche
US9434791B2 (en) 2009-12-11 2016-09-06 Contipro Pharma A.S. Method of preparation of an oxidized derivative of hyaluronic acid and a method of modification thereof
US9403918B2 (en) 2009-12-11 2016-08-02 Contipro Pharma A.S. Oxidized derivative of hyaluronic acid, a method of preparation thereof and a method of modification thereof
WO2012089179A1 (en) 2010-12-31 2012-07-05 Contipro Biotech S.R.O. Hyaluronan fibres, method of preparation thereof and use thereof
WO2013021249A1 (en) 2011-08-10 2013-02-14 Glycores 2000 S.R.L. Degradation-resistant cross-linked, low-molecular-weight hyaluronate
US9492586B2 (en) 2012-02-28 2016-11-15 Contipro Biotech S.R.O. Derivatives of hyaluronic acid capable of forming hydrogels
EP2644623A1 (de) * 2012-03-26 2013-10-02 Genewel Co., Ltd Implantationsmaterial mit biokompatiblem Polymer
US8822551B2 (en) 2012-03-26 2014-09-02 Genewel Co., Ltd. Implantation material comprising biocompatible polymer
US9522966B2 (en) 2012-08-08 2016-12-20 Contipro Biotech S.R.O. Hyaluronic acid derivative, method of preparation thereof, method of modification thereof and use thereof
WO2014056841A1 (en) 2012-10-09 2014-04-17 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Modified hyaluronic acid derivatives and use thereof
US9999678B2 (en) 2012-11-27 2018-06-19 Contipro A.S. C6-C18-acylated derivative of hyaluronic acid and method of preparation thereof
US10023658B2 (en) 2014-03-11 2018-07-17 Contipro A.S. Conjugates of oligomer of hyaluronic acid or of a salt thereof, method of preparation thereof and use thereof
US10617711B2 (en) 2014-06-30 2020-04-14 Contipro A.S. Antitumor composition based on hyaluronic acid and inorganic nanoparticles, method of preparation thereof and use thereof
US10689464B2 (en) 2015-03-09 2020-06-23 Contipro A.S. Self-supporting, biodegradable film based on hydrophobized hyaluronic acid, method of preparation and use thereof
US10759878B2 (en) 2015-06-15 2020-09-01 Contipro A.S. Method of crosslinking of polysaccharides using photoremovable protecting groups
US10414832B2 (en) 2015-06-26 2019-09-17 Contipro A.S Derivatives of sulfated polysaccharides, method of preparation, modification and use thereof
US10618984B2 (en) 2016-06-27 2020-04-14 Contipro A.S. Unsaturated derivatives of polysaccharides, method of preparation thereof and use thereof
WO2020039008A1 (fr) * 2018-08-22 2020-02-27 Natvi Procédé de lubrification
FR3085164A1 (fr) * 2018-08-22 2020-02-28 Natvi Procede de lubrification
US11857702B2 (en) 2018-08-22 2024-01-02 Natvi Lubrication method

Also Published As

Publication number Publication date
US4716224A (en) 1987-12-29
EP0161887A3 (en) 1986-10-08
DE3583963D1 (en) 1991-10-10
EP0161887B1 (de) 1991-09-04

Similar Documents

Publication Publication Date Title
US4716224A (en) Crosslinked hyaluronic acid and its use
EP0167363B1 (de) Vernetzte Glykosaminoglykane und ihre Verwendung
US5036056A (en) Methods for treating damaged corneal, uterine, or cartilage tissue
US4303676A (en) Hyaluronate based compositions and cosmetic formulations containing same
RU2174985C2 (ru) Полисахарид с привитым антиоксидантом и способ его получения
FI96610C (fi) Menetelmä hyaluronihapon täydellisesti tai osittain silloitettujen esterien valmistamiseksi
US8877243B2 (en) Cross-linked polysaccharide composition
KR870001901B1 (ko) 히알루론산 에스테르와 그 염의 제조방법
US4486416A (en) Protection of human and animal cells subject to exposure to trauma
US20100098794A1 (en) Topical anti-wrinkle and anti-aging moisturizing cream
EP0640647A2 (de) Ionisch vernetzte Gele aus Glykosaminoglykan zur Vermehrung von Weichgewebe und Arzneimittelabgabe
AU708758B2 (en) Anti-adhesion agent
ES2660847T3 (es) Ésteres fórmicos butíricos mezclados de polisacáridos ácidos, y su preparación y uso como cosméticos para la piel
LU101045B1 (en) Method for the manufacture and use of a bionic hydrogel composition for medical applications
US6486140B2 (en) Agents, and methods employing them, for the prevention or reduction of tissue adhesion at a wound site
WO1989000044A1 (en) Artificial lacrima
US20180228703A1 (en) Improved Hyaluronan and Modified-Hyaluronan in Biomedical Applications
JPS60233101A (ja) 架橋ヒアルロン酸
DE3650152T2 (de) Viskoelastische Kollagenlösung für augenheilkundige Verwendung und Verfahren zur Herstellung.
JP2015507070A (ja) 部分的に解重合したグリコサミノグリカン銀及び金塩
JPS5857319A (ja) 高粘性ヒアルロン酸製剤
CA1140469A (en) Hyaluronate based compositions and cosmetic formulations containing same
WO1989000043A1 (en) Ophthalmic agent and related compositions and method for treatment of the cornea
RU2098079C1 (ru) Глазной гель
AU2004229592B2 (en) Cross-linked polysaccharide composition

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): DE FR GB SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): DE FR GB SE

17P Request for examination filed

Effective date: 19870406

17Q First examination report despatched

Effective date: 19881012

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): DE FR GB SE

ET Fr: translation filed
REF Corresponds to:

Ref document number: 3583963

Country of ref document: DE

Date of ref document: 19911010

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
EAL Se: european patent in force in sweden

Ref document number: 85303183.9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20000502

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20000503

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20000504

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20000510

Year of fee payment: 16

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20010503

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20010504

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20010503

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20020131

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20020301